IL-21 enhances influenza vaccine responses in aged macaques with suppressed SIV infection.

Natural aging and HIV infection are associated with chronic low-grade systemic inflammation, immune senescence, and impaired antibody responses to vaccines such as the influenza (flu) vaccine. We investigated the role of IL-21, a CD4+ T follicular helper cell (Tfh) regulator, on flu vaccine antibody response in nonhuman primates (NHPs) in the context of age and controlled SIV mac239 infection. Three doses of the flu vaccine with or without IL-21-IgFc were administered at 3-month intervals in aged SIV+ NHPs following virus suppression with antiretroviral therapy. IL-21-treated animals demonstrated higher day 14-postboost antibody responses, which associated with expanded CD4+ T central memory cells and peripheral Tfh-expressing (pTfh-expressing) T cell immunoreceptor with Ig and ITIM domains (TIGIT), expanded activated memory B cells, and contracted CD11b+ monocytes. Draining lymph node (LN) tissue from IL-21-treated animals revealed direct association between LN follicle Tfh density and frequency of circulating TIGIT+ pTfh cells. We conclude that IL-21 enhances flu vaccine-induced antibody responses in SIV+ aged rhesus macaques (RMs), acting as an adjuvant modulating LN germinal center activity. A strategy to supplement IL-21 in aging could be a valuable addition in the toolbox for improving vaccine responses in an aging HIV+ population

Validation Aspects of Water Treatment Systems for Pharmaceutical Products

The goal of conducting validation is to demonstrate that a process, when operated within established limits, produces a product of consistent and specified quality with a high degree of assurance. Validation of water treatment systems is necessary to obtain water with all desired quality attributes. This also provides a framework to establish a total control over the process which monitors safety, efficacy and ultimately, the process outcomes. The present overview is an attempt to discuss various aspects of validation including different approaches, components of water treatment systems, equipment qualifications, phases of performance testing, documentation and post-validation monitoring.Keywords: Validation; Water treatment systems; Quality attributes; Pharmaceutical product

Late-time acceleration in Higher Dimensional Cosmology

We investigate late time acceleration of the universe in higher dimensional cosmology. The content in the universe is assumed to exert pressure which is different in the normal and extra dimensions. Cosmologically viable solutions are found to exist for simple forms of the equation of state. The parameters of the model are fixed by comparing the predictions with supernovae data. While observations stipulate that the matter exerts almost vanishing pressure in the normal dimensions, we assume that, in the extra dimensions, the equation of state is of the form $P \propto \, \rho^{1 - \gamma}$. For appropriate choice of parameters, a late time acceleration in the universe occurs with $q_0$ and $z_{tr}$ being approximately -0.46 and 0.76 respectively.Comment: 10 pages, 5 figure

Rescue medication use as a patient-reported outcome in COPD: a systematic review and regression analysis.

BACKGROUND: Reducing rescue medication use is a guideline-defined goal of asthma treatment, however, little is known about the validity of rescue medicine use as a marker of symptoms in chronic obstructive pulmonary disease (COPD). To improve patient outcomes, greater insight is needed into the relationship between rescue medication use and alternative COPD outcomes. METHODS: A systematic search of electronic databases (Embase®, MEDLINE® and Cochrane CENTRAL) was conducted from database start to 26 May, 2015. Studies of bronchodilator therapy with a duration of ≥24 weeks were included if they reported either mean change from baseline (CFB) in rescue medication use in puffs/day or % rescue-free days (%RFD), and at least one other COPD endpoint. Correlation and meta-regression analyses were undertaken to test the association between rescue medication use and other COPD outcomes using weighted means (weights proportional to the sample size of the treatment group) and unweighted means (equal weight for each treatment group). Each association was assessed at 6 months and study end. RESULTS: Forty-six studies involving 46,531 patients provided mean data from 145 treatment groups for evaluation. Changes in both measures of rescue medication use were correlated with changes in trough forced expiratory volume in one second ([FEV1]; Pearson correlation coefficients |r| ≥ 0.63; p < 0.0001) and with St George's Respiratory Questionnaire (SGRQ) score (|r| ≥ 0.70; p < 0.0001) at study end. Change in rescue medication use in puffs/day during the study correlated with annualized rates of moderate/severe exacerbations at 6 months and study end (both r = 0.66; p ≤ 0.0028). CFB in puffs/day was not well correlated with Transition Dyspnoea Index (TDI), but %RFD did correlate with TDI score at 6 months and study end (both r = 0.69; p < 0.0001). The values for CFB in puffs/day corresponding to the proposed minimal clinically important differences for trough FEV1 and SGRQ score were -1.3 and -0.6 puffs/day, respectively. A -1.0 puffs/day CFB in rescue use corresponded to a change of 0.26 events/patient-year in moderate/severe exacerbations. CONCLUSION: This analysis provides clear evidence of associations at a patient group level between rescue medication use and other clinically important COPD outcomes

Prediction of the Levodopa Challenge Test in Parkinson's Disease Using Data from a Wrist-Worn Sensor.

The response to levodopa (LR) is important for managing Parkinson's Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson's Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies

Effects of a scalable home-visiting intervention on child development in slums of urban India: evidence from a randomised controlled trial

Background: An estimated 63.4 million Indian children under 5 years are at risk of poor development. Home visits that use a structured curriculum to help caregivers enhance the quality of the home stimulation environment improve developmental outcomes. However, achieving effectiveness in poor urban contexts through scalable models remains challenging. Methods: Using a cluster randomised controlled trial, we evaluated a psychosocial stimulation intervention, comprising weekly home visits for 18 months, in urban slums of Cuttack, Odisha, India. The intervention is complementary to existing early childhood services in India and was run and managed through a local branch of a national NGO. The study ran from August 2013 to July 2015. We enrolled 421 children aged 10–20 months from 54 slums. Slums were randomised to intervention or control. Primary outcomes were children's cognitive, receptive language, expressive language and fine motor development assessed using the Bayley‐III. Prespecified intent‐to‐treat analysis investigated impacts and heterogeneity by gender. Trial registrations: ISRCTN89476603, AEARCTR‐0000169. Results: Endline data for 378 (89.8%) children were analysed. Attrition was balanced between groups. We found improvements of 0.349 of a standard deviation (SD; p = .005, stepdown p = .017) to cognition while impacts on receptive language, expressive language and fine motor development were, respectively, 0.224 SD (p = .099, stepdown p = .184), 0.192 SD (p = .085, stepdown p = .184) and 0.111 (p = .385, stepdown p = .385). A child development factor improved by 0.301 SD (p = .032). Benefits were larger for boys. The quality of the home stimulation environment also improved. Conclusions: This study shows that a potentially scalable home‐visiting intervention is effective in poor urban areas

Insulin Resistance and Gray Matter Volume in Neurodegenerative Disease

The goal of this study was to compare insulin resistance in aging and aging-related neurodegenerative diseases, and to determine the relationship between insulin resistance and gray matter volume (GMV) in each cohort using an unbiased, voxel-based approach. Insulin resistance was estimated in apparently healthy elderly control (HC, n = 21) and neurodegenerative disease (Alzheimer’s disease (AD), n = 20; Parkinson’s disease (PD), n = 22) groups using Homeostasis Model Assessment of Insulin Resistance 2 (HOMA2) and intravenous glucose tolerance test (IVGTT). HOMA2 and GMV were assessed within groups through General Linear Model multiple regression. We found that HOMA2 was increased in both AD and PD compared to the HC group (HC vs. AD, p = 0.002, HC vs. PD, p = 0.003), although only AD subjects exhibited increased fasting glucose (p = 0.005). Furthermore, our voxel-based morphometry analysis revealed that HOMA2 was related to GMV in all cohorts in a region-specific manner (p < 0.001, uncorrected). Significant relationships were observed in the medial prefrontal cortex (HC), medial temporal regions (AD), and parietal regions (PD). Finally, the directionality of the relationship between HOMA2 and GMV was disease-specific. Both HC and AD subjects exhibited negative relationships between HOMA2 and brain volume (increased HOMA2 associated with decreased brain volume), while a positive relationship was observed in PD. This cross-sectional study suggests that insulin resistance is increased in neurodegenerative disease, and that individuals with AD appear to have more severe metabolic dysfunction than individuals with PD or PD dementia